By far the single greatest risk factor for the development of osteoarthritis (OA) is age. A mechanism to explain this relationship, however, has not yet been identified. Advanced glycation end (AGE) products accumulate in human articular cartilage with increasing age and are degraded and released in association with OA. In published studies AGE products were shown to stimulate cytokine expression. Similarly in preliminary studies we have shown that human articular chondrocytes express cytokines in response to stimulation with soluble AGE products and also express the AGE receptor (RAGE) thought to mediate this activity. These observations suggest that AGE products released from articular cartilage have the potential to exacerbate articular cartilage degeneration characteristic of OA by activation of chondrocyte degradative pathways. Studies in Other tissues suggest the effect of AGE products is moderated by endocytic removal of damaging AGE products2 Preliminary studies suggest this might also occur in human articular cartilage and might serve to dampen the effect of AGE products on chondrocyte activation. This application proposes to further characterize the effect of AGE products on articular chondrocytes from normal donors and OA patients. It also proposes to characterize the effect of AGE products on chondrocyte gene expression focusing on cytokines and other genes know to be expressed in association with the development of OA. The role of the AGE receptor, RAGE, in this process will be determined. The second part of the proposal will determine if chondrocytes are able to detoxify AGE products by endocytic uptake and degradation. The receptors involved and the role of this pathway in abrogating the damaging effects of AGE products will be determined. This proposal examines whether AGE dependent chondrocyte activation might contribute to cartilage degradation in OA and whether endocytic removal and degradation of AGE products can abrogate this effect. This new pathway of cartilage degradation has the potential to explain, at least in part, the association between OA and old age. Future characterization of the pathway should provide targets for the rational development of therapeutic strategies aimed at preventing progressive cartilage destruction associated with OA.